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Table of Contents
Year : 2019  |  Volume : 16  |  Issue : 4  |  Page : 247-249

An unusual occurrence of deriphyllin-induced hallucinations: Contingency of concern

1 Department of Surgery, Apollo Hospital, Bhat, Ahmedabad, Gujarat, India
2 Department of Pharmacology, Smt. NHL Medical College, Ahmedabad, Gujarat, India
3 Department of Neurosurgery, Apollo Hospital, Bhat, Ahmedabad, Gujarat, India

Date of Submission29-Aug-2019
Date of Acceptance11-Nov-2019
Date of Web Publication12-Dec-2019

Correspondence Address:
Deepak S Malhotra
Department of Pharmacology, Smt. NHL MMC, Ellis-Bridge, Ahmedabad - 380 006, Gujarat
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/am.am_52_19

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Deriphyllin has been a mainstay of asthma therapy despite its narrow therapeutic index and a large pharmacokinetic variability between patients. Here, the authors decided to report a rare case of suspected deriphyllin-induced hallucinations in adults for the first time. An 83-year-old male patient who was a known case of recent onset asthma was on tablet deriphyllin 150 mg BD and salbutamol nebulization BD. He underwent emergency drainage of subdural hematoma due to a history of fall 20 days back with head injury. Within 2 days, he improved and was discharged 3 days later with the medicines. On follow-up after 7 days, he was admitted with a chief complaint of hallucinations. After stopping tablet deriphyllin, the patient's condition drastically improved in next few days and neurology was completely normal. Drug dechallenge was positive in this case since the hallucinations subsided after discontinuation of suspected drug deriphyllin. There are no such cases published previously.

Keywords: Deriphyllin, drug dechallenge, elderly, visual hallucinations

How to cite this article:
Dahiya M, Parikh NR, Malhotra DS, Sood SV. An unusual occurrence of deriphyllin-induced hallucinations: Contingency of concern. Apollo Med 2019;16:247-9

How to cite this URL:
Dahiya M, Parikh NR, Malhotra DS, Sood SV. An unusual occurrence of deriphyllin-induced hallucinations: Contingency of concern. Apollo Med [serial online] 2019 [cited 2022 Dec 7];16:247-9. Available from: https://apollomedicine.org/text.asp?2019/16/4/247/272821

  Introduction Top

Deriphyllin is a combination of etophylline and theophylline (1,3-dimethylxanthine) from methylxanthine group. These are extensively prescribed in developing countries like ours because it is inexpensive. It is a nonselective phosphodiesterase inhibitor, an effect that could simulate beta receptor stimulation by increasing intracellular levels of cyclic-AMP.[1] It can indirectly stimulate both β1 and β2 receptors through release of endogenous catecholamines.[2] Theophylline has narrow therapeutic index and a large pharmacokinetic variability between patients which makes toxicity a common problem. Adverse effects may be evident within the normal therapeutic range.[3] Drug-induced hallucination is a relatively common symptom, with a prevalence of 4%–38%.[4] Scientific literature is also scarce, reporting hallucinations in children occurring with deriphyllin. To our knowledge, this is the first report which associates deriphyllin use with hallucinations in adults.

  Case Report Top

An 83-year-old male patient with a history of fall 20 days back with head injury arrived in emergency department with drowsiness, altered sensorium, and left side weakness, along with urine and stool incontinence. On examination, his Glasgow Coma Scale was E3V4M6 with bilateral pupil 1.5 mm and reactive. Power on his right side was found to be 5/5 and left side 2/5. The patient is a known case of recent onset asthma and was on tablet deriphyllin 150 mg BD and salbutamol nebulization BD. The patient was started on antibiotics, analgesics, and antiepileptics. Computed tomography (CT) scan brain was done which showed right frontotemporoparietal subdural hematoma. He underwent emergency drainage of subdural hematoma. The patient's condition improved by evening, and no neurological deficit was found, with movement of all four limbs (power grade 5/5 on the right side and 4/5 on the left side). He was shifted to the ward next day, but he again developed weakness of left side for which CT scan was done which showed recurrent subdural clots for which he again underwent burr holes and evacuation of clots. Within 2 days, left side hemiparesis improved and then the patient was discharged 3 days later with the following medicines: tablet deriphyllin 150 mg BD, tablet levetiracetam 500 mg TDS, tablet metronidazole 400 mg TDS, tablet domperidone 10 mg + pantoprazole 20 mg, tablet folic acid 5 mg OD, tablet sporlac TDS.

On follow-up after 7 days, he was admitted to the emergency department with a complaint of irrelevant talk like driving a scooter and asking people to give him side (hallucination). The patient was subjected to CT brain and electrolytes along with other routine investigations. CT brain showed complete resolution of subdural hematoma. Electrolytes and other routine investigation were within normal range. Tablet levetiracetam was stopped and the patient was put on tablet sodium valproate. Despite this patient's hallucinations continued for next few days, tablet deriphyllin was stopped. After stopping tablet deriphyllin, the patient's condition drastically improved in next few days, and after 1 week, the patient's neurology was completely normal. Dechallenge was positive since the hallucination subsided after discontinuation of offending drug deriphyllin; hence, according to the WHO causality assessment criteria,[5] the reaction was probable/likely due to deriphyllin. This adverse drug reaction (ADR) was reported to the nearest ADR monitoring center with unique ID NO: 2019-48461.

  Discussion Top

Many factors, both intrinsic (age and disease state) and extrinsic (concurrent drugs, diet, viral infections, and cigarette smoking) affect the biotransformation of the drug in the liver. Some of these factors tend to decrease theophylline elimination, leading to accumulation of the drug in the body and to adverse effects. Genetic factor modifies drug metabolism as well as elimination of theophylline at therapeutic dose.[6] The elderly and the very young are more likely to experience toxicity from the recommended doses of theophylline.[7] In our case, the patient was 83-year-old elderly male, recently started with deriphyllin for recent onset asthma.

After theophylline treatment has been initiated, therapeutic drug monitoring is required.[8] Elderly patients or those with previous brain injury or neurological disease may be at increased risk of neurological changes.[9] Theophylline clearance may be reduced by interaction with various other drugs and the dose of theophylline may need to be reduced to prevent toxic effects.[10] In our case, no potential drug–drug interaction was identified.

Theophylline crosses the blood–brain barrier and mediates effects through blockade of adenosine synthesis and A1-receptor antagonism with consequent relative cellular hypoxia which may aggravate theophylline toxicity.[11]

Theophylline affects the cardiovascular, central nervous (CN), gastrointestinal, pulmonary, musculoskeletal, and metabolic systems. Neurological symptoms include tremors (most common), restlessness, agitation, hallucinations, headaches, irritability, and seizures. In addition to seizures, various types of hallucinations such as visual, auditory, and other psychotic and depressive symptoms have been reported.[12]

The association of hallucinations with theophylline has not been previously reported in adults at therapeutic doses. Baker studied theophylline toxicity in children who showed CN system manifestations including seizures in four patients and visual hallucinations in two patients in acutely intoxicated patients. Neither patient had received any medicine other than theophylline within the previous 24 h, and neither had a febrile illness at the time of presentation.[13] The patient in question here also reported visual hallucination as stated in the case report, but it was with the therapeutic dose.

It is sometimes difficult to establish if hallucination is caused by a drug or by an underlying illness. This is the first case report of deriphyllin-induced hallucination, which was reported at therapeutic doses, and no such cases of deriphyllin-induced hallucination are published previously. Hallucinations in this case resolved promptly after withdrawal of the suspected drug theophylline. Hence, there was a temporal relationship between drug discontinuation and resolving of hallucinations. The elderly, and those with a previous history of psychiatric illness, are at increased risk of drug-induced hallucination. Hallucinations caused by drugs are commonly visual.[13] This occurrence is in concordance with our case. The authors would like to point out a limitation of case report that the theophylline levels could not be measured, so it reduces the strength of association of this ADR to theophylline.

  Conclusion Top

Physicians should be careful about drugs with narrow therapeutic index like theophylline when prescribed to patients especially in extremes of age. As it is an unusual occurrence at therapeutic dose, a probable genetic factor modifying drug metabolism of deriphyllin could be responsible.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Goodman L, Gilman A. The Pharmacologyical Basis of Therapeutics: Pulmonary Pharmacology. Ch. 40., 13th ed. New York: McGraw-Hill; 2018. p. 733-4.  Back to cited text no. 1
Fisher J, Graudins A. Intermittent haemodialysis and sustained low-efficiency dialysis (SLED) for acute theophylline toxicity. J Med Toxicol 2015;11:359-63.  Back to cited text no. 2
Paloucek FP, Rodvold KA. Evaluation of theophylline overdoses and toxicities. Ann Emerg Med 1988;17:135-44.  Back to cited text no. 3
Ohayon MM. Prevalence of hallucinations and their pathological associations in the general population. Psychiatry Res 2000;97:153-64.  Back to cited text no. 4
The use of the WHO-UMC System for Standardised case Causality Assessment. Available from: http://www.WHO-UMC.org/graphics/4409.pdf. [Last accessed on 2019 Aug 20].  Back to cited text no. 5
Miller CA, Slusher LB, Vesell ES. Polymorphism of theophylline metabolism in man. J Clin Invest 1985;75:1415-25.  Back to cited text no. 6
Aitken ML, Martin TR. Life-threatening theophylline toxicity is not predictable by serum levels. Chest 1987;91:10-4.  Back to cited text no. 7
Ohnishi A, Kato M, Kojima J, Ushiama H, Yoneko M, Kawai H, et al. Differential pharmacokinetics of theophylline in elderly patients. Drugs Aging 2003;20:71-84.  Back to cited text no. 8
Olson KR, Benowitz NL, Woo OF, Pond SM. Theophylline overdose: Acute single ingestion versus chronic repeated overmedication. Am J Emerg Med 1985;3:386-94.  Back to cited text no. 9
Parfitt K, William M. Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press; 1999.  Back to cited text no. 10
Dragunow M. Adenosine receptor antagonism accounts for the seizure-prolonging effects of aminophylline. Pharmacol Biochem Behav 1990;36:751-5.  Back to cited text no. 11
Burkle WS, Gwizdala CJ. Evaluation of “toxic” serum theophylline concentrations. Am J Hosp Pharm 1981;38:1164-6.  Back to cited text no. 12
Baker MD. Theophylline toxicity in children. J Pediatr 1986;109:538-42.  Back to cited text no. 13


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